Amplification and/or overexpression of erbB2 (or HER2/neu) occur in approximately 25-30% of invasive breast cancer and are significantly associated with a worse prognosis. Mechanistic studies suggest that increased resistance to treatment and enhanced metastatic potential are the major mechanism by which erbB2 contributes to breast tumorigenesis. However, erbB2 does not act in isolation. Another closely related receptor erbB3 frequently co-expresses and interacts with erbB2 to activate the oncogenic signaling, such as PI-3K/Akt pathway and others, and subsequently promote breast cancer progression. Nonetheless, the crucial downstream mediators of erbB3 signaling in erbB2-positive (erbB2+) breast cancer remain elusive. We have reported that the erbB3/PI-3K/Akt signaling confers paclitaxel resistance in erbB2+ breast cancer cells via specific upregulation of Survivin, a vital inhibitor of apoptosis. Our recent studies on the underlying mechanism discover that elevated expression of erbB3 decreases and inhibition of erbB3 signaling with shRNA, a blocking antibody (Ab), or an Akt inhibitor increases the expression of two Survivin-targeting miRNAs, miR-203 and miR-542-3p in erbB2+ breast cancer cells. Interestingly, both miR-203 and miR-542-3p have been identified as tumor suppressive miRNAs and are frequently downregulated due to promoter methylation in various cancers, including breast cancer. Bioinformatic analysis suggests that in addition to Survivin, these two miRNAs also co-target a cohort of critical genes, such as ABCG2, ZEB2, and Snail, responsible for drug resistance and tumor metastasis. Thus, we hypothesize that activation of erbB3 signaling promotes erbB2+ breast cancer progression via epigenetic silencing of the Survivin-targeting miR-203 and miR-542-3p. This proposal aims to explore the molecular basis of erbB3 signaling-induced reduction of miR-203/miR-542-3p, and determine the anti-tumor activity of miRNA-replacement therapy in combination with paclitaxel against erbB2+ breast cancer.
ErbB2-mediated resistance to chemo-therapeutic agents, such as paclitaxel is one of the major clinical obstacles to effectively treat breast cancer patients whose tumors overexpress erbB2. Our recent studies suggest that the Survivin-targeting miR-203 and miR-542-3p plays a pivotal role in erbB3/PI-3K/Akt signaling-mediated paclitaxel resistance in breast cancer treatment. The current proposal will determine the therapeutic potential of a novel approach - miRNA-replacement therapy in combination with paclitaxel against the aggressive erbB2+ breast cancer. The mechanistic studies will not only identify miR-203 and miR-542-3p as the crucial downstream mediators of erbB2/erbB3 signaling, but also yield new avenues to develop novel strategies for the treatment of erbB2+ breast cancer. PUBLIC HEALTH RELEVANCE: Our studies will determine miR-203 and miR-542-3p as the crucial downstream mediators of erbB3 signaling, and thus shed new lights on breast cancer biology regarding the frequent co-expression of erbB2/erbB3 receptors. The data generated from this application will provide compelling evidence to develop a novel approach targeting Survivin for cancer treatment. We believe that miR-542-3p-replacement therapy in combination with paclitaxel will exert potent anti-tumor activity against erbB2+ breast cancer.